SUMMARY. Ischemic retinopathies (IRs), the leading cause of severe vision impairment in working-age Americans, remain a major public health concern. The recent introduction of therapies targeting the hyper-permeability factor (HPF), vascular endothelial growth factor (VEGF), has had a dramatic impact on the treatment of macular edema (ME) in patients with the two most common IRs, diabetes and retinal vein occlusions (RVOs). However, clinical trials assessing the efficacy of ?anti-VEGF? therapies have demonstrated limited improvement in vision in almost half of these patients despite treatment, underscoring the urgency to identify new, safe, and effective targets for the treatment of ME in IR patients. In this regard, the landmark discovery of hypoxia-inducible factor (HIF)-1?, a transcriptional enhancer that regulates the expression of hundreds of genes (including VEGF) that adapt hypoxic cells and ischemic tissues to conditions of low oxygen tension, has provided fundamental insight into the pathogenesis of IRs. Expression of HIF-1 is increased in retinal Mller glial cells in the inner retina in IR animal models as well as in IR patients, resulting in an increase in the expression of HIF-regulated genes. Nonetheless, several questions remain unanswered: 1) Is VEGF the only HIF-regulated gene that plays a (significant) role in the disruption of the integrity of the inner blood-retinal barrier (iBRB) and the promotion of ME in IR patients (i.e., is VEGF the only good HIF-regulated target for the treatment of ME?) 2) If not, which other HIF-regulated HPFs participate in the promotion of ME in IRs? 3) Are the expression levels of these other HPFs higher in the eyes of IR patients who respond inadequately to anti-VEGF therapies? 4) And finally, could targeting multiple factors be a more effective approach for the treatment of ME in IRs? The research proposed here will address these fundamental gaps in our knowledge. However, rather than confirming that known HPFs identified in other ischemic diseases are also expressed in IRs, our lab has set out to identify and comprehensively examine novel (understudied) HPFs that contribute to ME in these patients. Using an unbiased (agnostic) approach, we have been the first to identify Angiopoietin-like 4 (ANGPTL4) as a potent HPF upregulated by HIF in the hypoxic inner retina in IRs. This discovery could represent a paradigm shift in our understanding of the pathogenesis of ME and is significant because it exposes a novel therapeutic target for the treatment of ME in IR patients, including those who respond inadequately to anti-VEGF therapy. The objective of this proposal is to interrogate the molecular mechanisms by which ANGPTL4 promotes retinal vascular hyper-permeability with the final goal of designing novel therapeutic drugs to treat ME.